High-dosage extended-release formulation of gepirone

Abstract

The present invention relates to high-dosage extended-release formulation of gepirone and methods of treating major depression by administering the same to a subject in need thereof. More specifically, the present invention relates to a high-dosage extended-release tablet form of gepirone. The present invention also relates to a method of treating depression in mammals by administering to a subject in need thereof an effective amount the high-dosage extended-release formulation of gepirone in accordance with the present invention.

1 . A pharmaceutical composition, comprising: 
 (a) from about 14 to about 25 wt % gepirone, or bioactive metabolite thereof, as a free base or a pharmaceutically acceptable salt thereof;    (b) from about 70 to about 85 wt % of a pharmaceutically acceptable cellulosic polymer matrix; and    (c) suitable amounts of one or more pharmaceutically acceptable excipients, wherein the release rate of gepirone from the dosage form is such that about 18 to 24 hours are required to attain from about 90 to about 95% absorption of gepirone.    
   
   
       2 . The composition of  claim 1 , wherein (c) further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of colorant, microcrystalline cellulose, colloidal silica and magnesium stearate.  
   
   
       3 . The composition of  claim 1 , wherein (b) is hydroxypropylmethylcellulose having a viscosity of from about 15,000 cps to about 100,000 cps.  
   
   
       4 . The composition of  claim 1 , wherein the concentration of (a) ranges from about 15.5 to about 18.7 wt %.  
   
   
       5 . The composition of  claim 1 , wherein (a) is gepirone or a pharmaceutically acceptable salt thereof.  
   
   
       6 . The composition of  claim 1 , wherein (a) is a bioactive metabolite of gepirone or a pharmaceutically acceptable salt thereof.  
   
   
       7 . The composition of  claim 6 , wherein said bioactive metabolite of gepirone is selected from the group consisting of 3′-OH gepirone, 3′,5-dihydroxy gepirone, and 5-OH gepirone.  
   
   
       8 . A method of treating depression in a patient in need thereof, comprising administering to said patient an effective amount of the composition of  claim 1 .  
   
   
       9 . The method of  claim 8 , wherein said patient is human.  
   
   
       10 . The method of  claim 8 , wherein said patient further suffers from generalized anxiety.  
   
   
       11 . The method of  claim 8 , wherein said effective amount ranges from 0.01 to 40 mg/kg body weight per day.  
   
   
       12 . The composition of  claim 1 , wherein said composition is in a form of a tablet.  
   
   
       13 . The composition of  claim 12 , wherein the total weight of said tablet ranges from 350 to 450 mg.  
   
   
       14 . The composition of  claim 13 , wherein the weight of (a) in said table ranges from 60 to 80 mg.  
   
   
       15 . The composition of  claim 12 , wherein said tablet has an ovoid-rectangular shape with biconvex faces.  
   
   
       16 . The composition of  claim 15 , wherein said tablet has an overall dimension of 0.400±0.05 inches by 0.325±0.05 inches with a thickness of 0.240±0.025 inches.  
   
   
       17 . The composition of  claim 12 , wherein said tablet has an ovoid-rectangular shape with flat faces.  
   
   
       18 . The composition of  claim 17 , wherein said tablet has an overall dimension of 0.400±0.05 inches by 0.325±0.05 inches with a thickness of 0.195±0.025 inches.  
   
   
       19 . A method of treating depression in a patient in need thereof, comprising administering to said patient an effective amount of the composition of  claim 12 .  
   
   
       20 . The method of  claim 19 , wherein said patient is human.  
   
   
       21 . The method of  claim 19 , wherein said patient further suffers from generalized anxiety.  
   
   
       22 . The method of  claim 19 , wherein said effective amount ranges from 0.01 to 40 mg/kg body weight per day.  
   
   
       23 . A composition comprising: 
 (a) from about 14.0 to about 24.4 wt % gepirone, or bioactive metabolite thereof, as a free base or a pharmaceutically acceptable salt thereof,    (b) from 70.5 to 82.1 wt % hydroxypropylmethylcellulose having a viscosity of from about 15,000 to about 100,000 cps.,    (c) 0 to about 1 wt % colorant,    (d) about 8.0 to about 16.7 wt % microcrystalline cellulose,    (e) about 0.39 to about 0.47 wt % colloidal silica, and    (f) about 0.29 to about 1.0 wt % magnesium stearate.    
   
   
       24 . The composition of  claim 23 , wherein (a) ranges from about 15.5 to about 18.7 wt %.  
   
   
       25 . The composition of  claim 23 , wherein (a) is gepirone as a free base.  
   
   
       26 . The composition of  claim 23 , wherein (a) is a pharmaceutically acceptable salt form of gepirone.  
   
   
       27 . The composition of  claim 26 , wherein the pharmaceutically acceptable salt form of gepirone is gepirone hydrochloride.  
   
   
       28 . The composition of  claim 23 , wherein (a) is a bioactive metabolite of gepirone or pharmaceutically acceptable salt thereof.  
   
   
       29 . The composition of  claim 28 , wherein said bioactive metabolite of gepirone is selected from the group consisting of 3′-OH gepirone, 3′,5-dihydroxy gepirone, and 5-OH gepirone.  
   
   
       30 . The composition of  claim 23 , wherein (c) ranges from 0 to about 0.3 wt %.  
   
   
       31 . The composition of  claim 23 , wherein (c) is one or more iron oxides.  
   
   
       32 . The composition of  claim 23 , wherein (e) ranges from about 0.42 to about 0.47 wt %.  
   
   
       33 . A method of treating depression in a patient in need thereof, comprising administering to said patient an effective amount of the composition of  claim 23 .  
   
   
       34 . The method of  claim 33 , wherein said patient is human.  
   
   
       35 . The method of  claim 33 , wherein said patient further suffers from generalized anxiety.  
   
   
       36 . The method of  claim 33 , wherein said effective amount ranges from 0.01 to 40 mg/kg body weight per day.  
   
   
       37 . The composition of  claim 23 , wherein said composition is in a form of a tablet.  
   
   
       38 . The composition of  claim 37 , wherein the total weight of said tablet ranges from 350 to 450 mg.  
   
   
       39 . The composition of  claim 38 , wherein the weight of (a) in said table ranges from 60 to 80 mg.  
   
   
       40 . The composition of  claim 37 , wherein said tablet has an ovoid-rectangular shape with biconvex faces.  
   
   
       41 . The composition of  claim 40 , wherein said tablet has an overall dimension of 0.400±0.05 inches by 0.325±0.05 inches with a thickness of 0.240±0.025 inches.  
   
   
       42 . The composition of  claim 37 , wherein said tablet has an ovoid-rectangular shape with flat faces.  
   
   
       43 . The composition of  claim 42 , wherein said tablet has an overall dimension of 0.400±0.05 inches by 0.325±0.05 inches with a thickness of 0.195±0.025 inches.  
   
   
       44 . A method of treating depression in a patient in need thereof, comprising administering to said patient an effective amount of the composition of  claim 37 .  
   
   
       45 . The method of  claim 44 , wherein said patient is human.  
   
   
       46 . The method of  claim 44 , wherein said patient further suffers from generalized anxiety.  
   
   
       47 . The method of  claim 44 , wherein said effective amount ranges from 0.01 to 40 mg/kg body weight per day.  
   
   
       48 . A method of making a tablet of  claim 37  comprising: 
 (i) admixing all or a part of components (a) through (f),    (ii) blending the mixture obtained in (i),    (iii) adding a part of or the remainder of components (a) through (f),    (iv) blending the mixture obtained in (iii), if any components where added during (iii),    (v) slugging the blend from (iv),    (vi) milling the slug obtained in (v),    (vii) adding the remainder of component (f); if part reserved during (i) and (iv),    (viii) blending the mixture from (vii);    (ix) compressing the blend from (viii) to form tablet.    
   
   
       49 . A method of making a tablet of  claim 37  comprising: 
 i) admixing all of component (a), all of component (c), all of component (e), and 20% of the total concentration of component (b);    ii) blending the mixture from (i);    iii) adding to the blend from (ii) all of component (d), half of the total concentration of component (f), and the remaining 80% of the total concentration of component (b);    iv) blending the mixture from (iii);    v) slugging the blend from (iv);    vi) milling the slug from (v);    vii) adding the remaining 50% of component (f) to the milled slug from (vi);    viii) blending the mixture from (vii);    ix) compressing the blend from (viii) into the final desired form.    
   
   
       50 . The composition of  claim 37 , comprising: 
 (a) about 15.6 wt % of gepirone hydrochloride    (b) about 75.3 wt % hydroxypropylmethylcellulose,    (c) about 0.31 wt % yellow ferric oxide,    (d) about 8.0 wt % microcrystalline cellulose,    (e) about 0.42 wt % colloidal silica, and    (f) about 0.31 wt % magnesium stearate.    
   
   
       51 . The composition of  claim 50 , wherein the total weight of said tablet is 385 mg.  
   
   
       52 . The composition of  claim 51 , wherein the weight of (a) in said table is 60 mg.  
   
   
       53 . The composition of  claim 50 , wherein said tablet has an ovoid-rectangular shape with biconvex faces.  
   
   
       54 . The composition of  claim 53 , wherein said tablet has an overall dimension of 0.400±0.05 inches by 0.325±0.05 inches with a thickness of 0.240±0.025 inches.  
   
   
       55 . The composition of  claim 50 , wherein said tablet has an ovoid-rectangular shape with flat faces.  
   
   
       56 . The composition of  claim 55 , wherein said tablet has an overall dimension of 0.400±0.05 inches by 0.325±0.05 inches with a thickness of 0.195±0.025 inches.  
   
   
       57 . A method of treating depression in a patient in need thereof, comprising administering to said patient an effective amount of the composition of  claim 50 .  
   
   
       58 . The method of  claim 57 , wherein said patient is human.  
   
   
       59 . The method of  claim 57 , wherein said patient further suffers from generalized anxiety.  
   
   
       60 . The method of  claim 57 , wherein said effective amount ranges from 0.01 to 40 mg/kg body weight per day.  
   
   
       61 . The composition of  claim 37 , consisting essentially of: 
 (a) about 15.6 wt % of gepirone hydrochloride    (b) about 75.3 wt % hydroxypropylmethylcellulose,    (c) about 0.31 wt % yellow ferric oxide,    (d) about 8.0 wt % microcrystalline cellulose,    (e) about 0.42 wt % colloidal silica, and    (f) about 0.31 wt % magnesium stearate.    
   
   
       62 . The composition of  claim 61 , wherein the total weight of said tablet is 385 mg.  
   
   
       63 . The composition of  claim 62 , wherein the weight of (a) in said table is 60 mg.  
   
   
       64 . The composition of  claim 61 , wherein said tablet has an ovoid-rectangular shape with biconvex faces.  
   
   
       65 . The composition of  claim 64 , wherein said tablet has an overall dimension of 0.400±0.05 inches by 0.325±0.05 inches with a thickness of 0.240±0.025 inches.  
   
   
       66 . The composition of  claim 61 , wherein said tablet has an ovoid-rectangular shape with flat faces.  
   
   
       67 . The composition of  claim 66 , wherein said tablet has an overall dimension of 0.400±0.05 inches by 0.325±0.05 inches with a thickness of 0.195±0.025 inches.  
   
   
       68 . A method of treating depression in a patient in need thereof, comprising administering to said patient an effective amount of the composition of  claim 61 .  
   
   
       69 . The method of  claim 68 , wherein said patient is human.  
   
   
       70 . The method of  claim 68 , wherein said patient further suffers from generalized anxiety.  
   
   
       71 . The method of  claim 68 , wherein said effective amount ranges from 0.01 to 40 mg/kg body weight per day.  
   
   
       72 . The composition of  claim 37 , comprising: 
 (a) about 19.5 wt % of gepirone hydrochloride    (b) about 70.7 wt % hydroxypropylmethylcellulose,    (c-1) about 0.24 wt % yellow ferric oxide,    (c-2) about 0.61 wt % red ferrid oxide    (d) about 8.2 wt % microcrystalline cellulose,    (e) about 0.39 wt % colloidal silica, and    (f) about 0.29 wt % magnesium stearate.    
   
   
       73 . The composition of  claim 72 , wherein the total weight of said tablet is 410 mg.  
   
   
       74 . The composition of  claim 73 , wherein the weight of (a) in said table is 80 mg.  
   
   
       75 . The composition of  claim 72 , wherein said tablet has an ovoid-rectangular shape with biconvex faces.  
   
   
       76 . The composition of  claim 75 , wherein said tablet has an overall dimension of 0.400±0.05 inches by 0.325±0.05 inches with a thickness of 0.240±0.025 inches.  
   
   
       77 . The composition of  claim 72 , wherein said tablet has an ovoid-rectangular shape with flat faces.  
   
   
       78 . The composition of  claim 77 , wherein said tablet has an overall dimension of 0.400±0.05 inches by 0.325±0.05 inches with a thickness of 0.195±0.025 inches.  
   
   
       79 . A method of treating depression in a patient in need thereof, comprising administering to said patient an effective amount of the composition of  claim 72 .  
   
   
       80 . The method of  claim 79 , wherein said patient is human.  
   
   
       81 . The method of  claim 79 , wherein said patient further suffers from generalized anxiety.  
   
   
       82 . The method of  claim 79 , wherein said effective amount ranges from 0.01 to 40 mg/kg body weight per day.  
   
   
       83 . The composition of  claim 37 , consisting essentially of: 
 (a) about 19.5 wt % of gepirone hydrochloride    (b) about 70.7 wt % hydroxypropylmethylcellulose,    (c-1) about 0.24 wt % yellow ferric oxide,    (c-2) about 0.61 wt % red ferrid oxide    (d) about 8.2 wt % microcrystalline cellulose,    (e) about 0.39 wt % colloidal silica, and    (f) about 0.29 wt % magnesium stearate.    
   
   
       84 . The composition of  claim 83 , wherein the total weight of said tablet is 410 mg.  
   
   
       85 . The composition of  claim 84 , wherein the weight of (a) in said table is 80 mg.  
   
   
       86 . The composition of  claim 83 , wherein said tablet has an ovoid-rectangular shape with biconvex faces.  
   
   
       87 . The composition of  claim 86 , wherein said tablet has an overall dimension of 0.400±0.05 inches by 0.325±0.05 inches with a thickness of 0.240±0.025 inches.  
   
   
       88 . The composition of  claim 83 , wherein said tablet has an ovoid-rectangular shape with flat faces.  
   
   
       89 . The composition of  claim 88 , wherein said tablet has an overall dimension of 0.400±0.05 inches by 0.325±0.05 inches with a thickness of 0.195±0.025 inches.  
   
   
       90 . A method of treating depression in a patient in need thereof, comprising administering to said patient an effective amount of the composition of  claim 83 .  
   
   
       91 . The method of  claim 90 , wherein said patient is human.  
   
   
       92 . The method of  claim 90 , wherein said patient further suffers from generalized anxiety.  
   
   
       93 . The method of  claim 90 , wherein said effective amount ranges from 0.01 to 40 mg/kg body weight per day.